PINK1 regulation of neuronal and mitochondrial homeostasis PROJECT SUMMARY. Mutations in PTEN-induced kinase 1 (PINK1) cause familial autosomal recessive parkinsonism. As PINK1 plays a neuroprotective role in a wide range of genetic and toxin-induced Parkinson's disease (PD) models, studying its function in neurons may offer particular insights into potential therapeutic strategies. In the prior project period, we found that endogenous PINK1 exists in mitochondrial and cytosolic compartments. Moreover, these pools of PINK1 played divergent roles in regulating mitochondrial fission-fusion, mitophagy, calcium homeostasis and dendritic morphogenesis. Using primary neurons, differentiated neuronal cell lines and Pink1 knockout and control mice, the current proposal focuses on studying mechanisms by which PINK1 regulates neuron differentiation and the maintenance of extended axo-dendritic arbors. Based on preliminary data, we hypothesize that PINK1 interacts with cytosolic targets to regulate neuron differentiation and dendritic spine formation. We will study the role of novel PINK1-interacting proteins in regulating dendritogenesis and mitochondrial transport into neurites. The impact of PD-related mutations will be analyzed, and the neuroprotective potential of upregulating downstream pathways tested using Pink1-/- mice. Obtaining a better understanding of neuron-specialized functions of PINK1 in regulating dendritogenesis and compartmentalized mitochondrial content will yield valuable insights towards future strategies to reduce neuron dysfunction in PD.